marijuana medicinal purposes

Marijuana for Medicinal Purposes:An Evidence-Based Assessment

Prepared for Alberta's Workers' Compensation Board

Marijuana for Medicinal Purposes:An Evidence-Based Assessment

A Research Project Sponsored by Medical Services

Workers' Compensation Board Alberta

June, 2002

Research Team:

Bruce Fisher, MD, MSc, FRCP[C]

Don Johnston, MD, MSc, FRCP[C], Specialist, Occupational Medicine

Patricia Leake, MPP

The content, judgments and conclusions of this document are those of the members of the research teamand are not necessarily endorsed by WCB-Alberta.

Contents

Summary

I. Context 2

II. Assessing the scientific evidence 3

Research methodStudies meeting the inclusion criteriaFindings: potential therapeutic applications of herbal marijuanaFindings: potential harmful effects of herbal marijuanaSmoking marijuanaMarijuana research: challenges and limitations

III. Prescribing marijuana: challenges and limitations 19

IV. Marijuana for injured workers: potential therapeutic applications 20

V. Conclusion 20

Appendices 22

Appendix A Organizational statementsAppendix B Study designsAppendix C Comprehensive reviewsAppendix D Levels of evidence summaryAppendix E Worksheet for using an article about causation of harmAppendix F Worksheet for using an article about therapy or preventionAppendix G Psychoactive effect/therapeutic effectAppendix H Examples of ongoing marijuana research

Annotated Bibliography 37

References 62

SUMMARY

Systematic review of the literature reveals that scientific knowledge about herbal marijuana isincomplete, with insufficient evidence to determine its therapeutic potential or harmful effects.

There were few studies that met the review's quality inclusion criteria and that suggestedmedical utility of smoked herbal marijuana for some conditions. These studies yielded low levelevidence of questionable clinical importance and with dubious applicability to medical issuesrelated to the workplace. Furthermore, there have been significant advances in approvedtherapies since the 1970s and 1980s and herbal marijuana does not appear to providetreatment options not currently available with approved pharmaceutical drugs. Although theevidence for health risks associated with inhaled marijuana smoke had similar methodologicallimitations, the benefit to harm relationship of such long term use in chronic, non-life threateningconditions is uncertain and concerning.

Smoking marijuana is reported to reduce intraocular pressure in glaucoma and to amelioratepain, nausea, multiple sclerosis, spasticity and asthma. The evidence, however, comes fromsmall randomized control trials, or case control studies characterized by surrogate or short termoutcome assessments, comparisons to out-dated standards of care, and lack of considerationor measurement of benefit to harm relationships associated with long term inhaled marijuanause. The paucity and poor quality of the evidence make it difficult to compare herbal marijuanawith current pharmaceutical drugs that have received regulatory approval under much morerigorous experimental conditions.

Identified risks associated with herbal marijuana use include impairment of motor skills anddriving ability with an increased risk of motor vehicle accident culpability (particularly ifmarijuana and alcohol are used together), respiratory tract irritation (apparently reversible ifcannabis use is not prolonged), possible increased risk of aerodigestive cancers (especially ifthere is associated tobacco use) and the possibility of subtle cognitive impairment (of unknownreversibility) if marijuana use is long-term.

The concept of a predictable, quantifiable "dose" is a fundamental principle of medical therapy.Few (if any) of the prescribing criteria of medical pharmacology can be met in the case ofsmoked or ingested herbal marijuana: marijuana contains a variable mixture of poorly definedbiologically active compounds and the level of its active ingredient (9-tetrahydrocannabinol orTHC) fluctuates significantly between samples and is impossible to quantify by inspection.

Scientific knowledge about herbal marijuana is incomplete and appropriate rigorous randomizedcontrolled studies are needed to answer questions about marijuana's therapeutic potential.

Clinical trials of herbal marijuana are currently underway. As the results of each new trialbecome available, the study's "level of evidence" should be determined and the validity of itsresults, including clinical importance and applicability to Alberta's injured workers, should becritically appraised.

There is presently insufficient scientific evidence to treat marijuana as a "prescribable" drug.

ph07244SUMMARY

2I. Context

In July 2001, Canada became the first country in the world to adopt a federal system regulatingthe use of herbal marijuana for "medicinal purposes," codified in the Marihuana Medical AccessRegulations (the Regulations). The Regulations are controversial and many questions about"prescribing" marijuana remain unanswered (Appendix A).

Should herbal marijuana be treated as a prescribable drug"? This document evaluates thescope and quality of scientific evidence available for medical decision-makers. It is the result ofthe work of a collaborative, interdisciplinary research team that included Bruce Fisher, MD,Master of Science, Fellow of the Royal College of Physicians and Surgeons of Canada; DonJohnston, MD, Master of Science, Fellow of the Royal College of Physicians and Surgeons ofCanada and Specialist, Occupational Medicine; and Patricia Leake, Master of Pubic Policy.The information in this report was collected between September and December 2001.

Marijuana, the term for the dried flowering tops (buds) and leaves of the plant cannabis sativa,is a variable and complex mixture of more than 400 biologically active chemical compounds.Approximately 60 of these compounds are called cannabinoids. Cannabinoids appear in noother plant. Throughout this report, marijuana refers to unpurified plant material, includingleaves and flower tops, regardless of whether it is consumed by ingestion or by smoking.

The primary psychoactive ingredient in cannabis is the complex chemical 9-tetrahydrocannabinol (9-THC). Throughout this report, use of the acronym THC indicates 9-THC. The concentration of THC and other cannabinoids in marijuana varies significantlydepending on growing conditions, plant genetics and processing after harvest.

The psychological effects of cannabinoids include euphoria, anxiety reduction and sedation;these complicate both the study and the interpretation of other aspects of marijuanas effect.

Historically, plants and other natural products were the source of most medicinal substances.The effectiveness of these products was hampered, however, by variable and poorly definedconcentrations of active ingredients and by all manner of contaminants. As the science ofmedicinal chemistry evolved, it became possible to isolate the pure drug molecules so thatdrug dosage could be precise and side effects minimized.

Marijuana has been used as an herbal remedy for thousands of years by some estimates.There are questions about whether such traditional uses of marijuana are clinically justifiabletoday. Most scientific experts assert that marijuanas future as a drug lies primarily in itspharmacologically active and unique components, the cannabinoids, which can be isolated,subjected to scientific scrutiny and potentially developed as pharmaceutical drug products.Within the full set of approved pharmaceutical drug products available to patients there are twocommercially available pure drug molecules inspired by and related to herbal marijuana:dronabinol (brand name MARINOL), which contains chemically synthesized THC, and nabilone(brand name CESAMET), a synthetic cannabinoid. Both drugs are taken orally and must beprescribed by a physician (HC-RIAS 2001).

Herbal marijuana has not been reviewed by Health Canada for safety or effectiveness and hasnot been approved for sale as a therapeutic product in Canada.

Please note that both marijuana and marihuana are accepted spellings. We use marijuana in this document, except whenquoting directly from documents that use the spelling with the h.

ph07244I. Contextprescribed by a physician (HC-RIAS 2001).

3II. ASSESSING THE SCIENTIFIC EVIDENCE

Evidence-based medicine is the conscientious, explicit and judicious use of current bestevidence in medical decision-making. External clinical evidence both invalidates previouslyaccepted treatments and replaces them with new ones that are more powerful, more efficaciousand safer (Sackett 1996). In view of the limitations of anecdote, uncontrolled experience andunsystematic clinical observations, it is expected that clinical decision-making today will beguided by high quality scientific evidence.

The concept of a "hierarchy of evidence" is fundamental to evidence-based medicine. This is aschema for grading the evidence based on the tenet that different grades of evidence (studydesigns) vary in their predictive ability. Appendix B includes a brief discussion of study designs.

Not all studies using the same design are equally valid. Potentially useful evidence must becritically appraised: its scientific validity, clinical importance and applicability to the person orpopulation under consideration must be determined.

Research method

Stage 1: research context

Five recent comprehensive reviews on the subject of marijuana as a medicinal agent provided acontext for the task of assessing the primary research. The reviews are arranged in descendingchronological order in Table 1.

TABLE 1: Comprehensive Reviews

REVIEWING AGENCY TITLE DATE

American Medical Association Council on ScientificAffairs

Report to the AMA House of Delegates. Subject:Medical Marijuana

1997Updated:2001

Institute of Medicine (US) Marijuana and Medicine: Assessing the ScienceBase

1999

House of Lords (UK Parliament), Science andTechnology Committee 9th Report

Cannabis: The Medical and ScientificEvidence

1998

National Institutes of Health (US) Workshop on the Medical Utility of Marijuana 1997

British Medical Association Therapeutic Uses of Cannabis 1997

Each of these reports was prepared by a deliberative group of medical and scientific experts.While each report was written for a different purpose, all reached the same general conclusionsregarding herbal marijuana: while in certain forms it may be moderately effective in treating a

ph07244Research method

ph07244II. ASSESSING THE SCIENTIFIC EVIDENCE

4variety of symptoms, more research on the use of marijuana for "medicinal purposes" is neededand the use of whole and/or smoked marijuana as a medicine is not recommended. Moredetailed information on these reviews is found in Appendix C.

Stage 2: literature search

We searched the published, peer-reviewed literature using MEDLINE (1966-May 2001),EMBASE (1988-June 2001), the Cochrane Database of Systematic Reviews (2nd Quarter 2001),EBM Reviews-ACP Journal Club (1991 to March/April 2001) and the Database of Abstracts ofReviews of Effectiveness (1st Quarter 2001) through the OVID online system. The most recentsearch was completed in September 2001. The research team designed the search strategywith the assistance of a medical reference librarian at the J. W. Scott Health Sciences Library,University of Alberta, Edmonton, Alberta.

The search terms marijuana, cannabis and delta9-tetrahydrocannabinol were cross-searchedwith the terms therapeutic use, adverse effects, toxicity, clinical trials, fibromyalgia, multiplechemical sensitivity, mesothelioma, pain, chronic pain, glaucoma, chemotherapy, drug therapy,weight loss, spasticity, upper-aero-digestive cancer, immune system, bronchial neoplasms, lungneoplasms, prostate cancer, bladder cancer, digestive cancer and reproductive hormonalabnormalities. Terms were consistently exploded. Hedges or standardized searchstrategies based on research design were used to select the most valid studies from the searchresults. The search was not limited to the English language or to human studies or by age. Thisprocess resulted in a total of 546 titles.

Stage 3: review of abstracts and selection of articles for retrieval

Abstracts were screened and assessed independently by members of the research team.Reports that were obviously not relevant to the research question were excluded at this stage.Full text articles of abstracts identified as potentially relevant to the research question wereretrieved for appraisal. Reference lists from these articles were reviewed and full text articles ofrelevant citations were also retrieved for appraisal, for a total of 202 articles.

Stage 4: critical appraisal, including the selection and assessment of studies

The articles were divided into four groups: possible therapeutic potential, adverse effects, policyand review articles. Policy articles were set aside for separate evaluation. Members of theresearch team assessed the remaining articles independently. A study was recommended forinclusion at this stage if it was relevant to the research question, asked and answered aquestion in a systematic way, applied the scientific method (posited and evaluated hypothesesusing rational unbiased objective experimentation) and adhered to its study protocol. To beincluded, papers had to report on findings about crude herbal marijuana rather than a subset ofits molecular components: research on purified drug molecules such as THC, CESAMET andMARINOL was excluded. Sixteen harm studies and eight therapy studies met the inclusioncriteria. High quality review articles were identified and set aside for separate evaluation.

Stage 5: data extraction, levels of evidence

Structured abstracts (appended in the Annotated Bibliography) were produced for the sixteenharm and eight therapy studies using the Annals of Internal Medicine guidelines (Haynes 1990).Each studys level of evidence, validity of results, clinical importance and applicability were

ph07244 Stage 2: literature search

ph07244Stage 3: review of abstracts and selection of articles for retrieval

ph07244Stage 4: critical appraisal, including the selection and assessment of studies

ph07244 Stage 5: data extraction, levels of evidence

5evaluated independently by research team members, based on study type and studycharacteristics. Discrepancies were resolved by consensus.

Critical appraisal of the evidence was made with reference to documents produced by theEvidence-Based Medicine Working Group: Levels of Evidence Summary for Therapy, Harm orCausation (Appendix D), Worksheet for Using an Article about Causation of Harm (AppendixE) and Worksheet for Using an Article about Therapy or Prevention (Appendix F).

Studies meeting the inclusion criteria

Tables 2 and 3 present summaries and critical appraisal of the eight therapy studies and sixteenharm studies that met the inclusion criteria. Author, title and date, study type, authorsconclusions, critical appraisal by members of the research team and level of evidence areincluded for each study. Level of evidence is rated on a 1 (high level or strong evidence) to 5(low level or weak evidence) scale. Appendix D outlines the evidence rating system.

Findings: potential therapeutic applications of herbal marijuana

Chemotherapy-induced nausea and vomiting

Three studies related to marijuanas potential as an antiemetic met the inclusion criteria.Despite their methodological difficulties, they provide some evidence that smoked marijuana is amoderately effective antiemetic agent for patients undergoing cancer chemotherapy, especiallythose patients whose nausea has proved resistant to the antiemetic drugs used in the late1970s and early 1980s, when the research was conducted.

There are potential advantages to the use of antiemetics that can be delivered by inhalation.Patients with severe vomiting are sometimes unable to swallow or keep pills down long enoughfor the pills to take effect. The onset of drug effect is much faster with an antiemetic deliveredby inhalation (Joy 1999). On the other hand, a serious problem encountered in the New YorkState open trial with marijuana was the inability of nearly one-fourth of the patients to toleratesmoking marijuana (Vinciguerra 1988).

In the last decade, substantial progress has been made in controlling chemotherapy-inducednausea and vomiting, and none of the studies compared smoked herbal marijuana to thestandard care antiemetic therapies of today. It is therefore uncertain whether smoked marijuanais as effective as serotonin antagonists, currently considered the most effective antiemetics.Other unresolved issues include the types of nausea against which smoked marijuana is mosteffective and the degree of patient tolerance of the psychotropic side effects.

Glaucoma

The one study that met the inclusion criteria was published in 1975. At that time conventionalmedications for glaucoma caused a variety of adverse side effects, so there was much interestin the possible use of smoked marijuana in the treatment of glaucoma. Contemporaryconventional therapies for intraocular pressure outperform cannabinoids, however, and the nextgeneration of glaucoma drugs is expected to treat the disease even more effectively (Joy 2001).In addition, smoked marijuanas clinical utility in reducing intraocular pressure is compromisedby its short duration of action and accompanying side effects. The 1975 study did not addressthe issue of long-term effects of smoked marijuana.

ph07244Findings: potential therapeutic applications of herbal marijuana

ph07244Glaucoma

6TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY

STUDY STUDY TYPE AUTHORS CONCLUSIONS CRITICAL APPRAISAL LEVEL OFEVIDENCE

Analgesia

Greenwald MK. Antinociceptive,subjective and behavioral effects ofsmoked marijuana in humans.Drug Alcohol Depend 2000

Experimental randomizedplacebo-self -controlled clinicaltrial with five paidsubjects whoregularly smokedmarijuana.

While statistically significant, at the highest doses(producing substantial biological exposure), theantinociceptive effects of marijuana were ratherweak. The antinociceptive efficacy of marijuana ina human laboratory setting is probably marginal inrelation to its other biological, abuse-related,subject rejection and performance-impairingeffects.

Underpowered RCT. Eight potentialsubjects left the study after the firstsession because they found thehigher doses of marijuana intolerable.Although there is evidence that painsensation diminished at these levels,the side effects suggest thatmarijuana is a very questionabletreatment modality for this indication.Study used surrogate marker fornaturally occurring pain.

2b

Asthma

Tashkin DP. Bronchial effects ofaerosolized delta 9-tetrahydrocannabinol in healthy andasthmatic subjects. Am Rev RespirDis 1977

Experimental -randomizedcontrolled clinicaltrial.

The findings indicate that aerosolized 9-THC,although capable of causing significantbronchodilatation with minimal systemic sideeffects, has a local irritating effect on the airwayswhich may make it unsuitable for prolongedtherapeutic use.

Study looked at immediatepharmacologic reaction and wassilent on long term effects ofmarijuana smoke.

2b

Tashkin DP. Effects of smokedmarijuana in experimentally inducedasthma. Am Rev Respir Dis 1975

Experimental randomlyordered, singleblind placebocontrolled clinicaltrial.

Findings demonstrated acute airway dilation aftermarijuana smoking. Smoking does not appear tobe an appropriate long-term method foradministration of bronchodilator cannabinoidcompounds for potential therapeutic purposes.THC does not appear to be a suitablebronchodilator for therapeutic use because of itssystemic psychotropic and possible undesirableendocrine, immunologic and cytogenetic effects.

Study looked at immediatepharmacologic reaction and wassilent on long term effects ofmarijuana smoke.

2b

ph07244STUDIES MEETING THE INCLUSION CRITERIA: THERAPY

ph07244TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY

7TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)


Chemotherapy Induced Nauseaand Vomiting

Vinciguerra V. Inhalation marijuanaas an antiemetic for cancerchemotherapy. N Y State J Med1988

Prospective caseseries.

This preliminary trial suggests the usefulness ofinhalation marijuana as an antiemetic agent.Because of the lack of a randomized placebocontrol group, the precise role of this agent isunclear. Further studies should include derivativesof this substance in combination with standardeffective drugs to control chemotherapy-inducednausea and vomiting.

25% of the patients who initiallyconsented to the study refusedtreatment for a variety of reasons,most commonly because they did notwant to smoke marijuana.

4

Chang AE. A prospective evaluationof 9-tetrahydrocannabinol as anantiemetic in patients receivingadriamycin and cytoxanchemotherapy. Cancer 1981

Experimental -randomized,double blind, selfcontrol andplacebocontrolled trial oforal 9-THC andsmokedmarijuana.

The findings suggest that the antiemetic propertiesof THC are effective only against specificchemotherapeutic drugs.

The study was published in 1981 anddoes not compare herbal marijuanato current standard of care antiemetictherapies.

1b

Chang AE. Delta 9-tetrahydrocannabinol as anantiemetic in cancer patientsreceiving high-dose methotrexate. Aprospective, randomized evaluation.Ann Intern Med 1979

Experimental -randomized,double-blind,self-control andplacebo-controlled clinicaltrial.

9-THC appears to have significant antiemeticproperties when compared with placebo in patientsreceiving high-dose methotrexate.

The study was published in 1979 anddoes not compare herbal marijuanato current standard of care antiemetictherapies.

1b

8TABLE 2. STUDIES MEETING THE INCLUSION CRITERIA: THERAPY (Continued)


Glaucoma

Flom MC. Marijuana smoking andreduced pressure in human eyes:drug action or epiphenomenon?Invest Ophthalmol 1975

Experimental -double blindplacebo self-control clinicaltrial.

Analysis suggests an indirect effect of the drugassociated with relaxation - a psychophysiologicstate that can be produced by drug and non-drugmeans.

Effects of long-term use of marijuanaare not addressed by the study. Thisstudy was published in 1975 anddoes not compare herbal marijuanato current standard of care glaucomatherapies. Therapeutic use ofmarijuana for treatment of glaucomaseems premature considering thestate of knowledge of the drugsaction.

3b

Multiple Sclerosis and Spasticity

Greenberg HS. Short-term effects ofsmoking marijuana on balance inpatients with multiple sclerosis andnormal volunteers. Clin PharmacolTher 1994

Experimental - 2in 1 case series.

Marijuana smoking further impairs posture andbalance in patients with spastic MS.

Patients had the subjective feelingthat they were clinically improved,despite the fact that their posture andbalance were actually impaired bysmoking marijuana.

4

9TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM


Bronchial and Pulmonary Damage

Taylor DR. The respiratory effects ofcannabis dependence in youngadults. Addiction 2000

Outcomes studyat single timeinterval withexposure andoutcomedeterminedsimultaneously.

Significant respiratory symptoms and changes inspirometry occur in cannabis-dependent individualsat age 21 years, although the cannabis smokinghistory is of relatively short duration.

This study lacked a control group.The cannabis user group comprisedless than 10% of the total and two-thirds of this group also smokedtobacco. Generalizing from therelatively small sample size is difficult.

2c

Tashkin DP. Effects of smokedsubstance abuse on nonspecificairway hyperresponsiveness. Am RevRespir Dis 1993

Case-controlstudy of thepulmonary effectsof habitualsmoking of illicitsubstances.

No significant differences (as measured bymethacholine positive responses of 10%decreases from baseline FEV) to any concentrationof methacholine were found between marijuananonsmokers and smokers.

3b

Tashkin DP. Subacute effects ofheavy marihuana smoking onpulmonary function in healthy men. NEngl J Med 1976

Experimental self-control non-randomizedstudy.

These findings suggest that customary social useof marijuana may not result in detectable functionalrespiratory impairment in healthy young men,whereas very heavy marijuana smoking for six toeight weeks causes mild but statistically significantairway obstruction.

This study had a small sample sizeand all subjects were also heavytobacco smokers. Airway obstructionwas statistically but not clinicallysignificant.

4

ph07244TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM

10

TABLE 3. STUDIES MEETING INCLUSIONS CRITERIA: HARM (Continued)


Cognitive Impairment

Lyketsos CG. Cannabis use andcognitive decline in persons under 65years of age. Am J Epidemiol 1999

Observational -cohort study.This was a follow-up study of aprobabilitysample of theadult householdresidents of EastBaltimore.

Over long time periods, in persons under age 65years, cognitive decline occurs in all age groups.This decline is closely associated with aging andeducational level but does not appear to beassociated with cannabis use. The Mini-MentalStatus Examination (MMSE) is not a very sensitivemeasure of cognitive decline, however, and sosmall or subtle effects of cannabis use on cognitionor psychomotor speed may have been missed.

Although random sampling wasundertaken, no demographic tableswere provided to determine whether itwas successful. The degree ofexposure was not clear or likelyconsistent over time between groups.The MMSE is an insensitive measureof cognitive function.

2b

Fletcher JM. Cognitive correlates oflong-term cannabis use in CostaRican men. Arch Gen Psychiatry1996

Observational -cohort study.

Long-term cannabis use was associated withdisruption of short-term memory, working memoryand attentional skills in older long-term cannabisusers.

This small cohort study detectedsubtle disruption in memory andcognitive skills, but was unable todetermine the degree of confoundingbased on age-related changes alone,and studied a population not likelycomparable to that of the WCB.

2b

Block RI. Effects of chronicmarijuana use on human cognition.Psychopharmacology 1993

Observational cohort study.

More work is needed to evaluate alternativeinterpretations of the cognitive impairmentsassociated with heavy marijuana use.

This study of a mostly male low-income group had multipleconfounders, did not report a dose-response relationship and reportedoutcomes of unclear clinicalimportance.

2b

11



Psychomotor Impairment

Robbe H. Marijuanas impairingeffects on driving are moderate whentaken alone but severe whencombined with alcohol. HumPsychopharmacol Clin Exp 1998

Experimental -four single-blind,randomized,crossoverstudies.

Marijuana alone impairs driving performance, withthe degree of impairment increasing from small tomoderate as the THC dose increases from 100 to300 g/kg. However, when low to moderate dosesof THC (100 and 200 g/kg) are taken incombination with a Blood Alcohol Concentration(BAC) of about 0.04%, driving is severely impaired.

This small study reported onsurrogate markers of poor drivingperformance.

2b

Longo MC. The prevalence ofalcohol, cannabinoids,benzodiazepines and stimulantsamongst injured drivers and their rolein driver culpability. Part ii: Therelationship between drug prevalenceand drug concentration and driverculpability. Accid Anal Prev 2000

Case-controlstudy.

The study found a clear, concentration-dependentrelationship between alcohol and culpability. It alsofound a significant relationship betweenbenzodiazepines and culpability. In contrast, itfound no significant relationship between THC andculpability, although the data here and in otherculpability studies do not exclude the possibility ofan adverse effect of cannabinoids if theconcentration is sufficiently high.

3b

Yesavage JA. Carry-over effects ofmarijuana intoxication on aircraft pilotperformance: a preliminary report.Am J Psychiatry 1985

Experimental self-controlclinical trial.

The results may have implications for performanceof complex tasks the day after smoking marijuana.

This study was not randomized andlacked a control group.

4

12



Adverse Reproductive Effects

Scragg RK. Maternal cannabis use inthe sudden death syndrome. ActaPaediatr 2001

Observational anationwide casecontrol study.

Frequent maternal cannabis use may be a weakrisk factor for SIDS, but this finding requires furtherresearch.

The confidence intervals for the oddsratios for reported outcomes werewide and were not statisticallysignificant.

3b

Goldschmidt L. Effects of prenatalmarijuana exposure on child behaviorproblems at age 10. NeurotoxicolTeratol 2000

Case-controlstudy.

Prenatal marijuana exposure has an effect on childbehavior problems at age 10.

Prenatal marijuana may have aneffect on child behavior problems atage 10. This large case-series wasseriously confounded by the lack ofnon-ethanol and non-cannabis controlgroups.

3b

Shiono PH. The impact of cocaineand marijuana use on low birth weightand preterm birth: a multicenterstudy. Am J Obstet Gynecol 1995

Observational -prospectivemulticenter cohortstudy.

In this population of women receiving prenatalcare, cocaine use was uncommon and was notrelated to most adverse birth outcomes. Marijuanause was relatively common and was not related toadverse pregnancy outcomes. Tobacco is still themost commonly abused drug during pregnancy,and 15% of all cases of low birth weight in thisstudy could have been prevented if women had notsmoked cigarettes during pregnancy.

This large study was unable todemonstrate a harmful effect fromcannabis use.

2b

Gibson GT. Maternal alcohol,tobacco and cannabis consumptionand the outcome of pregnancy. AustN Z J Obstet Gynaecol 1983

Observational prospectivecohort study.

Cannabis used regularly, frequently and in its morepotent forms is significantly associated withpreterm labor and its sequelae (e.g. perinataldeath). Cannabis used in pregnancy is probablyassociated with intrauterine growth retardation.

This study was seriously confoundedby simultaneous tobacco and ethanoluse in cannabis smokers. When thiswas factored in there was notapparent association betweencannabis use and IUGR.

2b

13



Marijuana and schizophrenia

Martinez-Arevalo MJ. Cannabisconsumption as a prognostic factor inschizophrenia. Br J Psychiatry 1994

Observational study withoutcontrol group.

These data are consistent with other studies thatreport that cannabis consumption is associatedwith a poorer outcome of schizophrenia. Thenature of the association is unclear. Cannabis usemight be a result of the severity of theschizophrenia, so that patients with a pooreroutcome would consume more cannabissecondarily. On the other hand, cannabis could bea factor in relapse.

Increased use of cannabis may be amarker for schizophrenia, but it couldnot be determined from this studywhether the relationship wascorrelational or causal.

4

Upper Aero-Digestive Cancer

Zhang ZF. Marijuana use andincreased risk of squamous cellcarcinoma of the head and neck.Cancer Epidemiol Biomarkers Prev1999

Observational -case-controlstudy.

The results suggest that marijuana may increasethe risk of head and neck cancer with a strongdose-response pattern. Analysis indicated thatmarijuana use may interact with mutagensensitivity and other risk factors to increase the riskof head and neck cancer. The results need to beinterpreted with some caution in drawing causalinferences because of certain methodologicallimitations, especially with regard to interactions.

Although authors suggest thatmarijuana use may increase the riskof head and neck cancer with a trendtoward a dose-response pattern (wideconfidence intervals associated withpoint estimate), tobacco smoking mayhave been a confounder: 93% ofusers with cancer smoked tobacco,compared to 79% of non-users withcancer and 63% of the non-cancergroup.

3b

Sridhar KS. Possible role ofmarijuana smoking as a carcinogen inthe development of lung cancer at ayoung age. J Psychoactive Drugs1994

Exploratory case seriesstudy.

Exposure to marijuana smoke is associated withpresentation of cancer of the lung, particularly inyounger patients.

The population studied was from onepractice and 90% of the patients alsohad a tobacco smoking history.

4

14

Multiple sclerosis and spasticity

Marijuana is anecdotally reported to reduce the muscle spasticity associated with multiplesclerosis. However, clinical data reported in the single study meeting the inclusion criteria didnot confirm a therapeutic effect.

The double blind placebo-controlled study of postural responses in ten multiple sclerosispatients and ten healthy volunteers indicated that marijuana smoking impaired posture andbalance in both multiple sclerosis patients and volunteers. The patients subjective evaluationsof their improvement contrasted with objective measure of their physical performance. Althoughpatients had the subjective feeling that they were clinically improved, clinical measuresshowed that in fact marijuana smoking further impaired their posture and balance.

There is insufficient evidence to determine whether marijuana could yield useful medicines forspasticity. The paucity of universally effective medicine for muscle spasticity and anecdotalaccounts from marijuana users with multiple sclerosis and spinal cord injuries suggest the needfor carefully designed clinical trials to determine the role of cannabinoid drugs.

The regular use of smoked herbal marijuana would be contraindicated in a chronic condition likemultiple sclerosis.

Analgesia

There is a dearth of clinical pain research on herbal marijuana. There is no published evidencethat marijuana is superior to or equivalent to available therapies (NIH 1997).

Only one study in this area met the inclusion criteria. The study looked at experimentallyinduced pain. If information could be extrapolated, it would be to acute rather than to chronicpain. According to this study, in the laboratory setting, marijuana smoke showed antinociceptiveeffects only at the highest dose. The study raises the issue of intolerance to the dose eightpotential study subjects, all experienced marijuana users, left after the first session becausethey found the higher doses intolerable.

The small margin between clinical benefit and unacceptable adverse effects make this aquestionable therapeutic modality.

Marijuana as an anti-asthmatic agent

Two studies addressing the use of smoked marijuana as an anti-asthmatic agent met theinclusion criteria. Their results suggest that smoked marijuana has an acute bronchodilatoryeffect in both asthmatic and non-asthmatic individuals, and that asthma itself is apparently not acontraindication to the short term use of smoked marijuana.

Since these studies were conducted in the 1970s, more effective asthma therapies have beendeveloped. Neither of these studies provide evidence that long-term marijuana therapy wouldlead to long-term clinical improvement, as they focussed on immediate pharmacologic reaction,not long term effects of the many ingredients in marijuana smoke.

Despite this early suggestion of a therapeutic effect in asthma, marijuana has not been usedtherapeutically, nor has it been investigated as an anti-asthmatic agent by other than Tashkinand his colleagues. There is an understandable concern among clinical researchers that

ph07244Multiple sclerosis and spasticity

ph07244Analgesia

ph07244Marijuana as an anti-asthmatic agent

15

smoking is an unsuitable mode of administering any drug, and an especially inappropriate wayto administer a drug to patients with asthma, because it would inevitably involve the delivery ofother noxious chemicals that could nullify its therapeutic value in the short term and carry anincreased risk of respiratory disease and possibly cancer in the long term (Hall 1994).

Findings: potential harmful effects of herbal marijuana

Harmful effects of herbal marijuana depend, among other things, on the route of delivery, theduration of exposure and the "dose." They may be acute or chronic.

Effects on the respiratory system

The major concerns about the respiratory effects of cannabis use have been the possibleadverse effects of chronic, heavy marijuana smoking, including the production of chronicbronchitis as a precursor of irreversible obstructive lung disease and the possible causation ofcancers of the aerodigestive tract (including the lungs, mouth, pharynx, larynx and trachea) after20 to 30 years of regular marijuana smoking (Hall 1994).

Upper aerodigestive cancer

The evidence in the two articles that met the inclusion criteria is inconclusive. The studieslacked the necessary comparison groups to calculate the isolated effects of marijuana use oncancer risk. The numbers were very small and there was serious confounding with tobaccosmoking and alcohol use.

Despite the absence of such evidence, similarities between constituents of marijuana andtobacco smoke and the known latency periods between exposure and development ofaerodigestive tract cancers may be caveats to consideration of long term marijuana smoking formedical indications.

Bronchial and pulmonary damage

The four studies meeting the inclusion criteria were limited by design and none addressed thelong-term effects of marijuana smoking. Tobacco smoking was a confounder in most of thesestudies. Evidence of airway obstruction was not conclusive and demonstrated acute effects ofmarijuana smoking seem to be largely reversible.

Cognitive impairment

Two cognitive effects of cannabis must be distinguished: acute effects associated withintoxication and residual effects (both short and long term) persisting after the drug has left thecentral nervous system. The studies meeting the inclusion criteria examined marijuanasresidual effects.

Three studies on cognitive impairment met the inclusion criteria. Marijuana does not appear togrossly affect cognitive functions, although depending on the instrument used, it is possible todetect subtle impairments in intellectual and executive function with chronic marijuana use. It isnot clear whether there is a dose-response relationship.

The clinical and work-related implications of these findings are unclear, due to the manyconfounding variables, to the fact that acute cognitive effects of marijuana were not addressed

ph07244Findings: potential harmful effects of herbal marijuana

ph07244Effects on the respiratory system

ph07244Upper aerodigestive cancer

ph07244Bronchial and pulmonary damage

ph07244 Cognitive impairment

16

by the studies meeting the inclusion criteria, and to difficulty in applying results derived from thecognitive testing instruments to tasks performed in the workplace.

Reproductive effects of marijuana

Four epidemiological studies of the effects of marijuana smoking on reproduction met theinclusion criteria. Their results were mixed and conflicting.

Both the adverse reproductive outcomes and the prevalence of heavy marijuana use arerelatively rare events, so unless marijuana produces a large effect, very large sample sizeswould be required to detect adverse effects of cannabis. There may also be difficulties inidentifying marijuana smokers among pregnant women: the stigma associated with illicit druguse may discourage honest reporting (Hall 1994).

Studies were confounded by concomitant use of tobacco, alcohol and other illicit drugs andthere was a lack of control for income status, education and nutrition. These are all factorsknown to be associated with poorer obstetrical outcomes. Sources of confounding make itdifficult to unequivocally attribute any relationship between reproductive outcomes andmarijuana use to marijuana per se. The clinical significance of the singular effects of marijuanause remains unclear since these effects were small when compared with the effects of maternaltobacco use.

Marijuana and schizophrenia

The association between marijuana and schizophrenia is not well understood. One study aboutmarijuana and schizophrenia met the inclusion criteria. Increased use of cannabis may be amarker for schizophrenia, but it could not be determined from this study whether the relationshipwas correlational or causal.

Psychomotor impairment

The major potential health risk from the acute use of herbal marijuana (both for the user and forthe public) appears to arise from its effects on psychomotor performance.

Marijuana produces dose-related impairments in cognitive and behavioral functions that maypotentially impair driving a motor vehicle or operating machinery but the extent to whichcannabis contributes to traffic accidents is unknown. There are serious problems of causalattribution. Results of the three studies meeting the inclusion criteria were equivocal becausemost drivers who had cannabinoids in their blood also had high blood alcohol levels. The maineffect of marijuana use on driving may be to amplify the impairments caused by alcohol, whichis often used with the marijuana. Marijuana use may also impair users appraisal of their motorskills. Decreased performance on a complex task (simulated landing of an airplane) was notnoticed by participants, and patients with multiple sclerosis reported improvements incoordination despite any objective clinical improvement.

Smoking marijuana

Given the well-known consequences of smoking tobacco, it seems logical to suspect thatchronic marijuana smoking could also be detrimental to the respiratory system.

ph07244Reproductive effects of marijuana

ph07244Marijuana and schizophrenia

ph07244Psychomotor impairment

ph07244Smoking marijuana

17

Marijuana contains some 400 chemical compounds that convert into more than 2000substances when the plant material is burned, including carcinogens like benzene andbenzopyrene (Voelker 1994, PSFC 2002). Marijuana joints have been shown to deliver atleast four times as much tar to the lungs as tobacco cigarettes of equivalent weight. Thisdifference is due to the lack of filters on joints and because marijuana smokers typically inhalea larger volume of smoke and take it more deeply into the lungs than do tobacco smokers.Marijuana smokers also tend to hold smoke in for a time before exhaling, further increasingexposure to smoke and volatile toxins (Joy 2001).

On the other hand, because they are more tightly packed, commercial tobacco cigarettesproduce more smoke than hand rolled marijuana cigarettes. Most tobacco users typicallysmoke more cigarettes per day than their marijuana-using counterparts. Therefore, mosttobacco users take far more smoke into their lungs than people who smoke marijuanaexclusively (Joy 2001).

Since an estimated 70% of marijuana users also smoke tobacco, it is difficult to conductepidemiological studies that isolate the effects of marijuana on the respiratory system (Joy2001).

In principle, the respiratory risks of cannabis smoking could be eliminated if cannabis usersadopted the oral route. This seems unlikely to happen, however. Most long term users haveexperimented with ingested marijuana but continue to smoke it because it is a more efficientway to use cannabis and an easier way to titrate their dose of THC (Hall 1998). Onset ofpsychoactive and other pharmacologic effects of marijuana is rapid after smoking: THC in theform of an aerosol in the inhaled smoke is absorbed within seconds. In contrast, maximum THCand other cannabinoid levels are only reached one to three hours after ingesting marijuana.

Marijuana research: challenges and limitations

Marijuana research poses many challenges: one researcher has commented that designing atrial of herbal marijuana that will yield meaningful data is a trial in itself (Voelker 1994).

Assessment of potential harm: challenges and limitations

Evaluation of the health hazards of herbal marijuana is difficult for a number of reasons. Causalinferences about the effects of drugs on human health are difficult to make, especially whenthere is a long interval between use and alleged ill effects. Doses of illicit drugs consumed overperiods of years are difficult to quantify because of the varied strength of black market drugs,the dependence on subjective retrospective estimation of use and the stigma attached toadmitting to illicit drug use. Interpretation is further complicated by correlations betweenmarijuana, alcohol, tobacco and use of other illicit drugs.

Assessment of potential benefit: challenges and limitations

General research problems

Most human studies administered marijuana to relatively young, medically screened, healthymale volunteers well experienced in the effects of marijuana. Females rarely participated inmarijuana research completed to date (NIH 1997).

ph07244Marijuana research: challenges and limitations

ph07244inferences

18

In many instances research protocols to study marijuanas effects were required to useparticipants who already had experience with marijuana. In other cases, those who might havehad adverse reactions to marijuana chose not to participate in this type of study or werescreened out by the investigator. The incidence of adverse reactions to marijuana that mightoccur in people with no marijuana experience therefore cannot be estimated from these studies.

The "dose regimen" used for laboratory studies is another complicating factor. In mostinstances, laboratory research studies have looked at the effects of one or two "doses" ofmarijuana. These effects may well be different from those observed when the drug is takenrepeatedly for a chronic medical condition (Joy 1999).

Research problems that arise because marijuana is dried plant material

THC given orally alone in its pure form is the most thoroughly researched cannabinoid. Much ofwhat is written about the clinical pharmacology of crude herbal marijuana is actually inferredfrom the results of experiments using only the pure drug molecule THC. The result of thisstrategy is that a good deal is known about the pharmacology of ingested THC, butexperimental confirmation that the pharmacology of a smoked marijuana cigarette is indeedentirely or mainly determined by the amount of THC it contains remains to be completed.

Generally, in experiments actually using herbal marijuana, the assumed "dose" of herbalmarijuana is based only on the concentration of THC in the dried plant material. The amountsof cannabidiol and other cannabinoids in the plant also vary, however, and pharmacologicinteractions modifying the effects of THC may occur when herbal marijuana is used instead ofpure THC (NIH 1997). Furthermore, the compounds in smoked marijuana differ substantiallyfrom the compounds in the unburned plant material.

Dose is defined as the quantity (weight) of a pure drug molecule administered to a subject at agiven time. Standardizing "marijuana dosage" is difficult. The potency of the plant materialused in research studies is variable. Most of what is known about the pharmacology of smokedherbal marijuana comes from experiments with plant material containing about 2% THC, whichis less than the THC concentrations commonly found in marijuana today. Averageconcentrations are significantly higher and some samples have tested at up to 35% THC(Gieringer 1999). Thus a cigarette containing one gram of marijuana might contain anywherefrom 20 mgs of THC to 350 mgs of THC - an exceptionally wide variation.

Clinical trials carried out on herbal marijuana are unreliable if the sample has not been assayedfor active constituents. Not only would the dose of active component(s) be unknown orunstandardized, other constituents might have a modifying effect, either directly or by alteringthe pharmacokinetic parameters of the principal constituents, and mistakes have been made inusing unstandardized samples for clinical testing (Williamson 2000).

Research problems that arise because smoking is the common means of drug delivery

Besides potency of marijuana, other factors influence the amount of THC received in marijuanasmoke and produce significant changes in post-smoking plasma THC levels. Subjects smokingbehavior during an experiment is difficult for a researcher to control and may vary considerablybased on subjects' prior experience with marijuana. Variables like puff volume, breath-holdduration, number of puffs, inter-puff interval and inhalation volume (Azorlosa 1995) are noteasily quantified. A marijuana researcher attempting to control or specify the THC dose in a

19

pharmacologic experiment with smoked marijuana has only partial control over drug doseactually delivered (NIH 1997).

As with any smoked drug (e.g. nicotine or cocaine) characterizing the pharmacokinetics of THCand other cannabinoids from smoked marijuana is a challenge. Puff and inhalation volumeschange with the phase of smoking, tending to be highest at the beginning and lowest at the endof smoking a marijuana cigarette. During smoking, as the cigarette length shortens, theconcentration of THC in the remaining marijuana increases; thus each successive puff containsan increasing concentration of THC. One consequence of this process is that an experiencedmarijuana smoker can regulate almost on a puff by puff basis the dose of THC delivered tolungs and brain to obtain the desired psychological effects and avoid overdose and/or minimizethe undesired effects. A less experienced smoker is more likely to overdose or underdose (NIH1997).

Research problems that arise because marijuana has pronounced psychoactive effects

Objective measurement of positive therapeutic effect is difficult. A blinded study is problematicwith a psychoactive drug like marijuana, especially if the study involves subjects with previousmarijuana experience. One researcher gave up and simply noted that no placebo was used,since prior studies using the same cigarette found that 90% of the subjects could identify theactive drug (Yesavage 1985).

At the same time, there is uncertainty and disagreement about whether it is necessary orpossible to distinguish between marijuana's psychoactive and purported therapeutic effects(Appendix G). It the context of this debate, it may be useful to note that although in the 1970sacademic and pharmaceutical researchers made extensive attempts to develop new chemicallymodified cannabinoid molecules that separated the desired therapeutic effects from thepsychoactive properties of these substances, so far no such compound has been discovered(HLSCST 1998 Sec. 3.11).

III. PRESCRIBING MARIJUANA: CHALLENGES AND LIMITATIONS

Many of the factors that complicate marijuana research are also problematic for the medicalpractitioner who must decide whether to "prescribe" marijuana.

The concept of a predictable, quantifiable "dose" is a fundamental principle of medical therapy.Physicians are required to have knowledge of the amount of the pure drug compound in amedication, its uptake, distribution, absorption in the target tissue, its metabolism, half-life,metabolic products and interactions with other compounds, particularly with other medications.

Few (if any) of the prescribing criteria of medical pharmacology can be met in the case ofsmoked or ingested herbal marijuana: marijuana contains a variable mixture of poorly definedbiologically active compounds and the level of its active ingredient (9-tetrahydrocannabinol orTHC) fluctuates significantly between samples and is impossible to quantify by inspection.

The medical practitioner considering "prescription" of marijuana faces additional irregularities.Marijuana has not been reviewed for safety or effectiveness by health Canada and is not anapproved therapeutic product in Canada. Moreover, the evidence necessary to make informedmedical decisions about the relative harm and potential therapeutic value of marijuana islacking.

ph07244III. PRESCRIBING MARIJUANA: CHALLENGES AND LIMITATIONS

20

IV. MARIJUANA FOR INJURED WORKERS:POTENTIAL THERAPEUTIC APPLICATIONS

Two conceivable therapeutic applications of marijuana for injured workers are glaucoma that isunresponsive to conventional therapy and chemotherapy induced nausea and vomiting that isunresponsive to conventional therapy. A review of WCB-Alberta electronic claims data did notidentify any cases that meet these criteria.

Injured workers who experience chronic pain unresponsive to conventional therapy may raisequestions about "medicinal" use of herbal marijuana. Scientific evidence of the effectiveness ofmarijuana as a therapy for chronic pain, however, does not currently exist.

V. CONCLUSION

Systematic review of the literature revealed that scientific knowledge about herbal marijuana isincomplete, with insufficient evidence to determine its therapeutic potential or harmful effects.

There were few studies that met the reviews quality inclusion criteria and that suggestedmedical utility of smoked herbal marijuana for some conditions. These studies yielded low levelevidence of questionable clinical importance and with dubious applicability to medical issuesrelated to the workplace.

Smoking marijuana is reported to reduce intraocular pressure in glaucoma and to amelioratepain, nausea, multiple sclerosis spasticity and asthma. The evidence, however, comes fromsmall randomized control trials or case-control studies that are characterized by surrogate orshort term outcome assessments, comparisons to out-dated standards of care and lack ofconsideration or measurement of benefit to harm relationships associated with long term inhaledmarijuana use.

Furthermore, there have been significant advances in approved therapies since the 1970s and1980s, and herbal marijuana does not appear to provide treatment options not currentlyavailable with approved pharmaceutical drugs. The paucity and poor quality of the evidencemake it difficult to compare herbal marijuana with current pharmaceutical drugs that havereceived regulatory approval under much more rigorous experimental conditions.

Although the evidence for health risks associated with inhaled herbal marijuana smoke hadsimilar methodological limitations, the benefit to harm relationship of such long term use inchronic, non-terminal or life or limb threatening conditions remains uncertain and concerning.

Identified risks associated with herbal marijuana use include impairment of motor skills anddriving ability with an increased risk of motor vehicle accident culpability (particularly ifmarijuana and alcohol are used together), respiratory tract irritation (apparently reversible ifcannabis use is not prolonged), possible increased risk of aerodigestive cancers (especially ifthere is associated tobacco use) and the possibility of subtle cognitive impairment (of unknownreversibility) if marijuana use is long-term.

Scientific knowledge about herbal marijuana is incomplete and appropriate rigorous randomizedcontrolled studies are needed to answer questions about marijuana's therapeutic potential.

Clinical trials of herbal marijuana are currently underway (Appendix H). As the results of eachnew trial become available, the study's "level of evidence" should be determined, and the

ph07244IV. MARIJUANA FOR INJURED WORKERS:POTENTIAL THERAPEUTIC APPLICATIONS

ph07244V. CONCLUSION

21

validity of its results, including clinical importance and applicability to Alberta's injured workers,should be critically appraised.

There is presently insufficient evidence to treat marijuana as a "prescribable" drug.

22

APPENDIX A: ORGANIZATIONAL STATEMENTS

In November 1996, California voters enacted an initiative measure entitled the Compassionate Use Act of 1996. To ensure thatseriously ill Californians have the right to obtain and use marijuana for medical purposes, the statute created an exemption toCalifornia laws prohibiting the possession and cultivation of marijuana. Over the next five years, voters in Connecticut, Louisiana,New Hampshire, Ohio, Vermont, Virginia, Arizona, Alaska, Oregon, Nevada and Washington enacted "medical marijuana" initiatives.

In July 2001, Canada became the first country in the world to adopt a federal system regulating the use of herbal marijuana for"medicinal purposes," codified in the Marihuana Medical Access Regulations (the Regulations). In order for a patient to qualify, aphysician must complete and sign a medical declaration indicating the nature of the symptom for which he or she is recommendingmarijuana. The physician must also specify a marijuana dosage," (defined by Health Canada by weight of dry plant material) and aroute and form of administration to the patient.

Use of marijuana for medicinal purposes is controversial, and many questions about "prescribing" marijuana remain unanswered.Excerpts from statements made by of a number of North American organizations and agencies follow: organizations representingphysicians, organizations regulating physicians, governmental agencies and patient advocacy groups.

ph0724422APPENDIX A: ORGANIZATIONAL STATEMENTS

23

GOVERNMENTAL AGENCIES

Agency Statement (excerpt)

Health Canada . . . due to the health risks associated with the smoked form in particular, and due to the lack of evidence supporting theclaimed health benefits, access to marihuana will be granted under these Regulations in special medical circumstances only. . . The requirements will range from minimal, in the case of terminal illness situations, to more substantive for non-terminalillness cases where little or no conclusive scientific evidence exists . . .

Marihuana has not been reviewed for safety or effectiveness and has therefore not been approved for sale as a drug inCanada or any other country. Most scientific experts assert that marihuanas future as a drug lies primarily in itspharmacologically active components, the cannabinoids. These chemicals can be isolated, subjected to scientific scrutinyand potentially developed as standardized pharmaceutical drug products . . . Much of the evidence of the potentialtherapeutic effects of smoked marijuana is heavily anecdotal. Scientific studies supporting the safety and efficacy ofmarihuana for therapeutic use are often inconclusive (HC-RIAS 2001).

Canadian Institutes ofHealth Research

. . . evidence of potential therapeutic effect of smoked marijuana is heavily anecdotal. While there are reports of thetherapeutic value of smoked marijuana, scientific studies supporting the safety and efficacy of marijuana for therapeuticclaims are inconclusive . . . based on existing data, the use of smoked marijuana for therapeutic indications should not beconsidered outside of controlled clinical trials (CIHR 2000-2001).

ph0724423GOVERNMENTAL AGENCIES

24

ORGANIZATIONS REGULATING CANADIAN PHYSICIANS: COLLEGES OF PHYSICIANS AND SURGEONS

College Statement (excerpt)

College of Physiciansand Surgeons ofBritish Columbia

The alleged medical benefits of smoked marijuana are hitherto unproven and are based on anecdotal information . . . Thelack of availability of credible scientific information on the indications for smoked marijuanas medicinal use, together with theabsence of information on the risks and benefits of the substance, make it questionable, if not dangerous, for physicians toprescribe this agent for their patients. Little is known about the interaction of this agent with other drugs or medications. Itsanalgesic effects alone are reported to be no better than codeine. What is known is that THC potentiates the analgesicaction of narcotics many-fold. That fact alone requires that it be used very cautiously and may indicate a potential for harm.Marijuana is also known to create dependency or to be addictive for a significant number of its users.

Physicians are advised that they should not prescribe any drug for their patients without knowing the risks, benefits, potentialcomplications and drug interactions associated with the use of that agent. Currently, that would certainly include marijuanain its smoked form, where it may cause significant harm. Furthermore, physicians may be the subject of accusations orsuggestions of negligence, including liability, if a prescribed drug, including prescribed marijuana, produces unforeseennegative effects. . . The regulations for prescribing marijuana recently published by Health Canada do not take into accountthe requirement for physicians to follow evidence based protocols and guidelines in providing care for their patients.Smoked marijuana has not been the subject of the investigative protocols and the pre-public release requirement requiredfor all new drugs (VanAndel 2001).

College of Physiciansand Surgeons ofManitoba

The alleged medical benefits of smoking marijuana are not proven and are based mainly on anecdotal information. Thereare three categories of symptoms for which marijuana may be prescribed for medicinal purposes, yet the extensive list ofconditions which arise out of these three categories encompasses medical conditions for which there is not good scientificevidence supporting the use of marijuana. . . Based on the available scientific evidence, the medicinal use of smokedmarijuana is at present generally without valid scientific foundation and physicians should not feel obligated to recommend,support or prescribe this substance (CPSM 2001).

Collge desmdecins du Qubec

The federal government seems to have forgotten that the physician is a scientist who treats patients using methods thathave been subjected to tried and tested procedures. Indeed, the new Marijuana Medical Access Regulations are theoutcome of a court decision, and not scientific evidence. Physicians need not respond to politico-legal trickery or involvethemselves in this issue as long as there are no precise data on the posology, safety, and effectiveness of this treatment.Yet, the Minister of Health seems to have foisted this hot potato on them (Lamontagne 2001).

ph0724424ORGANIZATIONS REGULATING CANADIAN PHYSICIANS: COLLEGES OF PHYSICIANS AND SURGEONS

25

ORGANIZATIONS REPRESENTING CANADIAN PHYSICIANS

Medical Associationor Organization

Statement (excerpt)

Alberta MedicalAssociation

These regulations announced by Health Canada are unacceptable because there has not been thorough and rigorousscientific testing. This, in turn, may negatively affect the physician-patient relationship: patients may believe that they couldbenefit from use of marijuana for one of a number of conditions, or that they may be able to obtain marijuana for recreationaluse through their physician. There are several reasons why the AMA finds these new regulations unacceptable: this methodof treatment is not evidence-based and has not yet had any rigorous testing of long-term implications, there are no clinicalpractice guidelines in place for the medicinal use of marijuana including appropriate dosage, physicians have no way ofknowing product potency (or consistency of same), and they place physicians in an untenable position (Steed 2001).

Canadian MedicalAssociation

The CMA supports access to any therapy proven safe and effective and manufactured with appropriate diligence. I alsowant to make clear that we understand the needs of those individuals who may have gained, or hope to gain, benefit fromthe use of marijuana to ameliorate medical symptoms or who have exhausted other proven therapies. We recognize that aregulatory scheme for medicinal use of marijuana must exist. However, these regulations are placing Canadian physiciansand their patients in the precarious position of attempting to access a product that has not gone through the normalprotocols of rigorous pre-market testing (Barrett 2001).

Canadian MedicalProtectiveAssociation

The CMPA believes the medical declarations under the regulations place an unacceptable burden on member physicians toinform themselves as to the effectiveness of medical marijuana in each patients case, as well as the relative risks andbenefits of the drug and what dosage would be appropriate. This information is simply not available. In medicine,knowledge is typically derived from clinical trials, of which we understand there are very few for marijuana. Given the factthat many physicians would not have the necessary knowledge about the effectiveness, risks or benefits of marijuana, webelieve it is unreasonable to make physicians gatekeepers in this process (Gray 2001 Nov).

ph0724425ORGANIZATIONS REPRESENTING CANADIAN PHYSICIANS

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ORGANIZATIONS REPRESENTING CANADIAN PHYSICIANS (continued)

Medical Associationor Society

Statement (excerpt)

Canadian Society ofAddiction Medicine

Although there is anecdotal, pre-clinical and limited controlled evidence that cannabis products may be effective in someconditions . . . this evidence is weak and existing studies have demonstrated significant side effects. There are alternativetherapies that have less risk of side effects for these conditions. Cannabis products are not first-line treatment for anyknown medical condition. Therefore, our Medicinal Use of Cannabis Products Policy Statement is:

Currently, available scientific information and clinical practice experience indicate that overall, there is more risk than benefit,in the use of cannabis products for medicinal purposes. Ongoing well-designed clinical research into the possible medicinaluses of cannabis products is essential, using the same rigorous standards that are applied to any therapeutic agent prior toits introduction into general clinical practice (CSAM 1999).

Physicians for aSmoke-Free Canada

Based on Health Canada's literature and the independent evidence available linking marijuana smoke to acute and chronichealth problems, the following conclusions can be drawn:

. . . Given the lack of substantial scientific data regarding the benefits of specific chemical compounds contained inmarijuana, marijuana cannot be considered a medicine in the conventional sense.

When considering applications for CDSA exemption, physicians cannot in good faith testify that the benefits of treatmentwith marijuana outweigh the risks.

The health risks associated with smoking marijuana are an appropriate reason for physicians to deny patients access tomarijuana for medicinal purposes (PSFC 2002).

Ontario MedicalAssociation

The Ontario Medical Association strongly objects to the Marijuana Medical Access Regulations . . . as they have thepotential to compromise patient safety and are not grounded in science. The medicinal use of marijuana should not beexpanded without proper scientific evidence of its benefits. These regulations are inconsistent with Health Canadasprocess of approving pharmaceuticals, which requires thorough scientific research before making drugs available topatients. The lack of sound research seriously compromises the physicians ability to appropriately advise patients (OMA2001).

27

ORGANIZATIONS REPRESENTING AMERICAN PHYSICIANS

Medical Associationor Academy

Statement (excerpt)

American Academyof Ophthalmology

Based on reviews by the National Eye Institute (NEI) and the Institute of Medicine on available scientific evidence, the TaskForce on Complementary Therapies believes that no scientific evidence has been found that demonstrates increasedbenefits and/or diminished risks of marijuana use to treat glaucoma compared with the wide variety of pharmaceuticalagents now available (AAO 1999).

American MedicalAssociation

The AMAs House of Delegates recently rejected a committee report that would have urged the organization to considercompassionate use of medical marijuana for cancer and other patients. The AMA declared that the scientific evidence waslacking to prove marijuanas usefulness in relieving symptoms like nausea in cancer patients and spasticity in MS patients . .. AMA Trustee Dr. Herman Abromowitz stated: To endorse something on the basis of anecdotal comments is not ourpolicy" (Stern 2001, Susman 2001).

California MedicalAssociation

CMA has consistently maintained its position that cannabis should be available for therapeutic use as a Schedule II drugonly if there are properly controlled studies proving it is efficacious. CMA believes that seriously ill patients should not beoffered a treatment whose efficacy may be illusory and which in some cases may actually worsen the patients medicalcondition. Therefore, CMA has opposed the medicalization of cannabis unless and until there is objective proof that suchuse is scientifically justifiable (CMALC 2001).

ph0724427ORGANIZATIONS REPRESENTING AMERICAN PHYSICIANS

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PATIENT ADVOCACY GROUPS

Patient AdvocacyGroup

Statement (excerpt)

American CancerSociety

Though marijuana smoke delivers THC and other cannabinoids to the body, it also delivers harmful substances, includingmost of those found in tobacco smoke. In addition, plants contain a variable mixture of biologically active compounds andcannot be expected to provide a precisely defined drug effect. For these reasons, chemically-defined drugs that act on thecannabinoid receptors of the brain are likely to provide the safe and most effective cannabinoid . . . The American CancerSociety does not advocate the use of inhaled marijuana or the legalization of marijuana (ACS 1999).

In an article entitled Experts: Pot Smoking is not Best Choice to Treat Chemo Side-Effects, Dawn Willis, director of researchand communication for the American Cancer Society noted that considering that many cancer patients undergoingchemotherapy today will survive their disease, patients would be unwise to increase risk of another cancer by smokingmarijuana" (ACS 2001).

Canadian CancerSociety

The Canadian Cancer Society supports the government in its efforts to provide clear criteria so that patients who qualify touse marijuana to alleviate symptoms of cancer or side effects of treatment will be permitted to do so. Whether or not aperson chooses to use marijuana to help them with their experience with cancer is an individuals choice and the Societyencourages people to discuss this with their doctor (CCS 2001).

National MultipleSclerosis Society(US)

In a 1997 statement, the National Multiple Sclerosis Societys Medical Advisory Board indicated that neither marijuana norits active ingredient can be recommended as a treatment for symptoms of MS. Studies done to date have not providedconvincing clinical evidence of benefit. Side effects, including memory impairment and personality change have been noted.Individuals concerned about the medicinal use of marijuana for MS should consult their personal physicians (NMSS 1999Mar).

In the summer of 1999, Dr. Nancy Holland, vice president of Clinical Programs at the Society noted that since multiplesclerosis is a lifelong chronic illness, not a terminal disease like AIDS, or a short-term crisis like severe nausea from cancerchemotherapy, the health dangers of smoked marijuana are significant for people with MS. We urge people to explore otheroptions for managing spasticity while research pushes forward for answers about the potential of the cannabinoids. Wehope this question will be settled by medical science, not by court cases or politics she said (King 1999).

ph0724428PATIENT ADVOCACY GROUPS

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APPENDIX B: STUDY DESIGNS

Studies may be classified into three broad groups by study design: experimental studies,observational studies and exploratory studies.

Experimental studies are also known as intervention studies or clinical trials. These areprospective studies involving human subjects designed to answer specific questions about theeffects or impact of a particular biomedical intervention. Randomized Controlled Trials (RCTs)are part of this group.

The outcome of a well designed clinical trial involves objective measurements wheneverpossible, using predetermined outcome measures or endpoints. The success or failure ofthe trial is measured by criteria established in a written protocol before the start of the trial.The trial should include a sufficiently large number of subjects to provide statisticallysignificant differences in outcome measures between placebo and drug-treated groups.

Observational studies explore a topic in order to generate basic statistics and hypotheses.Cross sectional studies, cohort studies and case control studies are part of this category.

Exploratory studies generate hypotheses for further and scientifically rigorous investigation.Case series and case reports, which look at individuals who manifest a particular healthproblem, are part of this category.

Higher grades of evidence are more likely to reliably predict outcomes. Inferences abouttherapy, for example, may be very strong if the results come from a systematic review of welldesigned, methodologically strong RCTs with consistent results. They are somewhat weaker ifthey are made based on a single RCT, unless it is very large and has enrolled a diverse patientpopulation. Because observational studies may under (or more typically over) estimatetreatment effects in an unpredictable fashion, their results are far less trustworthy than those ofRCTs. Unsystematic clinical observations (case series and case reports) provide the weakestinferences about treatment effects. Much of the evidence regarding the harmful effects of atherapy come from observational studies (Guyatt 2000).

ph07244APPENDIX B: STUDY DESIGNS

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APPENDIX C. Comprehensive Reviews

Based on exhaustive reviews of the scientific evidence, six panels of scientific and medical experts have released major reports on the subject of medicinal use ofherbal marijuana and purified cannabinoids in the last five years. In January 1997, the White House Office of National Drug Policy asked the Institute of Medicine(IOM) to conduct a review of the scientific evidence to assess the potential health benefits and risks of marijuana and its constituent cannabinoids. That reviewbegan in August 1997 and culminated with a report issued in 1999, Marijuana and Medicine, Assessing the Science Base (Joy 1999). Widely regarded as thelandmark study on the issue, it is being used to guide medical research around the world. The most recently updated report is the AMAs document, based on areview of the literature current to April 2001.

Reports are summarized below in tabular form, including their findings on marijuana's potential harms and possible therapeutic effects. Each of these reports waswritten for a different purpose, but all reached the same general conclusions regarding herbal marijuana: while in certain dosage forms it may be moderatelyeffective in treating a variety of symptoms, more research on the medical use of marijuana is needed, and the use of whole and/or smoked marijuana as amedicine is not recommended. The table below is adapted from Marijuana as Medicine? The Science Behind the Controversy (Joy 2001).

CANNABINOIDS AND MARIJUANA: RECENT CONCLUSIONS OF PANELS OF SCIENTIFIC AND MEDICAL EXPERTS

Reviewing Agency

Conditionsrecommended fortreatment in clinical trialsof smoked marijuana

Promising targets forcannabinoid drugs

Recommended researchon potential harms ofmarijuana andcannabinoids?

Use of whole and/orsmoked marijuana as amedicine

Primary goals ofcannabinoid drugdevelopment

American MedicalAssociation

2001 update1997 report

Various, including AIDS,wasting, chemotherapy-induced nausea andvomiting, MS, spinalcord injury, neuropathy,or chronic pain

Not discussed None recommended Not recommended

Smoke-free inhaleddelivery system formarijuana andcannabinoids

Institute of Medicine(US) 1999

Various, includingnausea and vomiting,wasting, pain

Various, includingnausea and vomiting,wasting, pain, andspasticity

Yes, especially onsmoking-related harms

Whole marijuana is nota modern medicine

Safe, reliable, rapid-onset delivery methodfor cannabinoids

UK ParliamentHouse of Lords SelectCommittee on Scienceand Technology1998

Multiple sclerosis,chronic pain Not discussed None recommended

Hazards of marijuanasmoke noted

Rapid-onset, smoke-freedelivery systems (e.g.,inhalation, under thetongue, and rectalsuppositories)

ph0724430APPENDIX C. Comprehensive Reviews

31

Reviewing Agency Conditionsrecommended fortreatment in clinical trialsof smoked marijuana

Promising targets forcannabinoid drugs

Recommended researchon potential harms ofmarijuana andcannabinoids?

Use of whole and/orsmoked marijuana as amedicine

Primary goals ofcannabinoid drugdevelopment

World HealthOrganization1997 Not discussed

Nausea and vomiting;spasticity

Various, includinginfertility, respiratorydamage, immunedysfunction,schizophrenia, andantimotivationalsyndrome

Hazards of marijuanasmoke noted Not discussed

National Institutes ofHealth (US)1997

Wasting, chemotherapy-induced nausea andvomiting, neurologicaland movementdisorders, glaucoma

Nausea and vomiting,neuropathy, possiblymuscle spasticity,certain dystonias andepilepsy None recommended

Should be held to samestandards of safety andefficacy as FDA-approved drugs

Smoke-free inhaleddelivery systems formarijuana andcannabinoids

British MedicalAssociation1997 Not discussed

Muscle spasticity,neurodegenerativedisorders, epilepsy None recommended

Cigarettes and crudemarijuana preparationsshould not be used Novel cannabinoid

analogs for new uses

Report of the Council on Scientific Affairs. 1997. Report to the AMA House of Delegates. Subject: Medical Marijuana. Updated with a review of articles published between 1997 andApril 2001 in Report 6 of the Council on Scientific Affairs (A-01).

Institute of Medicine. 1999. Marijuana and Medicine: Assessing the Science Base.

House of Lords (UK Parliament). 1998. Science and Technology Committee 9th Report. Cannabis: The Scientific and Medical Evidence. London: Her Majestys Stationary Office.

National Institutes of Health. 1997. Workshop on the medical utility of marijuana. Bethesda, Maryland: National Institutes of Health.

British Medical Association. 1997. Therapeutic uses of cannabis. Harwood Academic Publishers, United Kingdom.

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APPENDIX D

Levels of evidence summary for therapy harm or causation

Grade of Recommendation Level ofEvidence

Type of Study Study characteristics

1a Systematic review (withhomogeneity) of RCT

A systematic summary of the medical literature thatuses quantitative methods to summarize the results

1b Single RCT with narrowConfidence Interval

Randomized controlled trial. A group of patients israndomized to either experimental or control groups,which are followed for the variables or outcomes ofinterest

A

1c All-or-none case series Where all patients die or fail without intervention andsome survive or succeed with it

2a Systematic review (withhomogeneity) of cohort studies

2b Cohort study or poor quality orunder-powered RCT (e.g.

33

APPENDIX E

Worksheet for Using an Article About Causation of Harm

Citation: ________________________________________________________________

Grade/level of evidence: ____________________________________________

1. Are the results of the study valid? (yes/no/cannot tell)

A. Were there clearly identified comparison groups that were similar with respect toimportant determinants of outcome, other than the one of interest? (RCT, cohort,case-control? Other known prognosis factors similar or adjusted for?)

B. Were the outcomes and exposures measured in the same way in the groups beingcompared? (Recall bias? Interviewer bias? Exposure to opportunity similar?)

C. Was follow-up sufficiently long and complete? (Reasons for incomplete follow-up?Risk factors similar in those lost and not lost to follow-up?)

D. Is the temporal relationship correct? (Exposure preceded outcome?)

E. Is there a dose-response gradient? (Risk of outcome increases with quantity orduration of exposure?)

F. Overall, are the results of the study valid?

2. What are the results?

A. How strong is the association between exposure and outcome? Relative Risk?Odds Ratios?

B. How precise is the estimate of risk? (Confidence intervals?)

3. Will the results help in patient care?

A. Are the results applicable to injured workers in Alberta? Patients similar fordemographics, morbidity and other prognostic factors? Are treatments and exposuressimilar?

B. What is the magnitude of the risk? Absolute risk increase (and its reciprocal)?

C. On this basis should one attempt to stop the exposure? Strength of evidence?Magnitude of risk? Adverse effects of reducing exposure?

Based on a worksheet developed by the Evidence Based Medicine (EBM) Working Group. A complete list of members (withaffiliations) of the EBM Working Group appears in the first article in the "Users' Guides to the Medical Literature" series, JAMA 1993;270:2093-2095).

ph07244APPENDIX EWorksheet for Using an Article About Causation of Harm

34

APPENDIX F

Worksheet for Using an Article About Therapy or Prevention

Citation: ________________________________________________________________

Grade/level of evidence: ____________________________________________

1. Are the results valid? (yes/no/cannot tell)

A. Was the assignment of patients to treatment randomized?

B. Where all patients who entered the trial properly accounted for and attributed atits conclusion? Was follow-up complete? Were patients analyzed in the groups towhich they were randomized? Intention to treat analysis used?

C. Were patients, their clinicians and study personnel blind to treatment?

D. Were the groups similar at the start of the trial? Baseline prognostic factors(demographics, co-morbidity, disease severity, other known confounders) balanced? Ifdifferent, were these adjusted for?

E. Aside from the experimental intervention, were the groups treated equally? Co-intervention? Contamination? Compliance?

2. What are the results?

A. How large is the treatment effect? Absolute risk reduction? Relative risk reduction?

B. How precise is the estimate of the treatment effect? Confidence intervals?

3. Will the results help in patient care?

A. Can the results be applied to injured workers in Alberta? Patients similar fordemographics, severity, co-morbidity and other prognostic factors? Compelling reasonwhy they should not be applied?

B. Were all clinically relevant outcomes considered? Are substitute endpoints valid?

C. Are the benefits worth the harms and costs? Number needed to treat for differentoutcomes?

Based on a worksheet developed by the Evidence Based Medicine (EBM) Working Group. A complete list of members (withaffiliations) of the EBM Working Group appears in the first article in the "Users' Guides to the Medical Literature" series, JAMA 1993;270:2093-2095).

ph07244APPENDIX FWorksheet for Using an Article About Therapy or Prevention

35

APPENDIX G: PSYCHOACTIVE EFFECT / THERAPEUTIC EFFECT

There is uncertainty and disagreement about whether it is necessary or possible to distinguish betweenmarijuana's psychoactive and purported therapeutic effects.

The psychoactive effects of cannabis including euphoria, anxiety reduction and sedation reportedly domake some patients feel better. Marijuana diminishes to a large extent the subjective feeling of being ill(Neelman 1996) and some contend that the marijuana high should be considered an integral part ofmarijuana's therapeutic value:

My mom and I both have MS, and both live in Canada. Neither of us is applying for an exemptionbecause neither of use is sufficiently ill or sufficiently harmed by conventional pharms to make aworkable case for our MDs to back us . . . so we both smoke in fear . . . I think anyone with MSshould automatically qualify. It just adds so immensely to my overall sense of well being (NYT-DPF2001).

Dr. Mark Ware, a researcher heading an ongoing McGill University Pain Centre study of the benefits ofcannabis as a pain reliever, stated:

I dont think theres any reason why we should consider getting high as a negative side effect inpatients who are feeling dreadful, depressed and in a lot of pain and really suffering. Somethingwhich may reduce pain and make them feel better is not a bad thing (Nestruck 2001).

An editorial in the New England Journal of Medicine argues:what really counts for therapy with this kind of safety margin is whether a seriously ill patient feelsrelief as a result of the intervention, not whether a controlled trial proves its efficacy (Kassirer 1997).

Marijuanas known psychoactive effects could be at least partially responsible for the disjunction betweenanecdotes about feeling better and the sparse clinical evidence of marijuanas therapeutic value:

while formal clinical research has not conclusively shown that marijuana is effective . . . it appearsthat a number of patients who have tried the drug have found relief (Grey 1996).

Skeptics argue that:it is likely that the self-administration of marijuana smoke produces some or all of its purportedtherapeutic benefits through its non-specific reward mechanism (DuPont 1999).

The UK Parliament's House of Lords Select Committee on Science and Technology observed:it is natural to wonder whether the beneficial effects of cannabis reported by patients might simply berelated to the feeling of well-being caused by the intoxicant properties of the drug (HLSCST 1998Sec. 5.22).

The British Medical Association notes:it is somewhat paradoxical that cannabinoids are reported to be of therapeutic value in neurologicaldisorders . . . since very similar symptoms can be caused by cannabis itself . . . it is not clear howmuch of the reputed effects of cannabis in motor disorders are due to psychoactive or analgesiceffects (HLSCST 1998 Sec. 5.23).

In 1997, after an extensive review of the literature, the Health Council of the Netherlands' StandingCommittee on Medicine (HCNSCM) concluded:

the evidence is insufficient to justify the medicinal use of marijuana . . . patients themselves must bearthe full responsib

marijuana medicinal purposes

herbal marijuana use

herbal marijuana isincomplete

prescribing marijuana

scientific evidence

inhaled marijuana smoke

insufficient evidence

therapeutic potential

research methodstudies

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